Abstract 5079: Targeting cholecystokinin-2 receptor (CCK2R) for pancreatic ductal adenocarcinoma prevention in p48Cre/+-LSL-KrasG12D/+ mice model
Authors: Altaf Mohammed, Naveena B. Janakiram, Chen Suen, Nicole Stratton, Stanley Lightfoot, Anil Singh, Gopal Pathuri, Rebekah Ritchie, Venkateshwar Madka, Chinthalapally V. Rao
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that is difficult to treat. Hence, developing strategies that delay/inhibit/prevent the progression of pancreatic intraepithelial neoplasms (PanINs) to PDAC are of utmost importance. Gastrin signaling mediated through gastrin/cholecystokinin-2 receptor (CCK2R) and its down-stream signaling molecules are overexpressed in both human and KrasG12D mouse PDACs. Particularly, CCK2R is highly expressed in PDAC stellate cells and is involved in fibrosis and PDAC progression. Thus, targeting CCK2R for pancreatic chemoprevention is a valid approach for PDAC prevention. Two CCK2R antagonists, netazepide (YF476) and JNJ-26070109, were tested for their effect on PanINs and their progression to PDAC in p48Cre/+-LSL-KrasG12D/+ mice. Six-week-old p48Cre/+-LSL-KrasG12D/+ (22-24/group) mice were fed (AIN-76A) diets containing 0, 250 or 500 ppm netazepide or JNJ-26070109 for 38 weeks. After sacrifice at 44 weeks of age, pancreata were collected, weighed, and evaluated histopathologically for PanINs and PDAC. To understand the molecular mechanisms, levels of proliferation and apoptosis (PCNA, p21, and caspase3) were analyzed by Immunohistochemistry (IHC). Results demonstrated that control diet fed mice showed 69% and 33% incidence of PDAC in male and female mice. Dietary administration of low dose and high dose JNJ-26070109 inhibited the incidence of PDAC by 88% (p&amp;lt;0.003) and 71% (p&amp;lt;0.004) in male mice and by 100% and 24 % (not significant, p&amp;gt;0.05) in female mice respectively. Dietary administration of low dose and high dose netazepide inhibited the incidence of PDAC by 74% (p&amp;lt;0.018) and 69% (p&amp;lt;0.02) in male mice and by 45% and 33 % (not significant, p&amp;gt;0.05) in female mice, respectively. Both agents reduced PanIN 3 (carcinoma in-situ) multiplicity compared to untreated mice in both genders, with JNJ-26070109 showing greater inhibitory effect compared to netazepide. Both agents showed a decrease in caspase-3, p21, and PCNA expressions. Transcriptome analysis showed downregulation of Cldn1, Sstr1, Apod, Gkn1, Siglech, Cyp2c44, Bnc1, Fmo2, 623169, Kcne4, Slc27a6, Cma1, Rho GTPase activating protein 18 and Gpr85 genes in JNJ-26070109-treated mice compared to untreated mice. Netazepide-treated mouse pancreas specifically showed down regulation of Riks, Zpbp, Ntf3, Lrrn4, Aass, Skint3, Kcnb1, Dgkb, Ddx60, and Aspn genes compared to untreated mice pancreas. In summary, targeting the CCK2R pathway by netazepide and JNJ-26070109 showed significant chemopreventive effects in suppression of PDAC and PanIN3. Overall, JNJ-26070109 showed better chemopreventive efficacy on PDAC incidence and PanIN 3 multiplicity as compared to netazepide. However, caution is recommended while selecting the doses as the agents appeared to exhibit gender-specific effects. [Supported by NCICN25001-26} Citation Format: Altaf Mohammed, Naveena B. Janakiram, Chen Suen, Nicole Stratton, Stanley Lightfoot, Anil Singh, Gopal Pathuri, Rebekah Ritchie, Venkateshwar Madka, Chinthalapally V. Rao. Targeting cholecystokinin-2 receptor (CCK2R) for pancreatic ductal adenocarcinoma prevention in p48Cre/+-LSL-KrasG12D/+ mice model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5079.